title: Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons.
abstract: Activation of neurons in the midbrain periaqueductal gray (PAG) inhibits spinal dorsal horn neurons and produces behavioral antinociception in animals and analgesia in humans. Although dorsal horn regions modulated by PAG activation contain all three opioid receptor classes (mu, delta, and kappa), as well as enkephalinergic interneurons and terminal fields, descending opioid-mediated inhibition of dorsal horn neurons has not been demonstrated. We examined the contribution of dorsal horn mu-opioid receptors to the PAG-elicited descending modulation of nociceptive transmission. Single-unit extracellular recordings were made from rat sacral dorsal horn neurons activated by noxious heating of the tail. Microinjections of bicuculline (BIC) in the ventrolateral PAG led to a 60-80% decrease in the neuronal responses to heat. At the same time, the responses of the same neurons to iontophoretically applied NMDA or kainic acid were not consistently inhibited. The inhibition of heat-evoked responses by PAG BIC was reversed by iontophoretic application of the selective mu-opioid receptor antagonists, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). A similar effect was produced by naloxone; however, naloxone had an excitatory influence on dorsal horn neurons in the absence of PAG-evoked descending inhibition. This is the first demonstration that endogenous opioids acting via spinal mu-opioid receptors contribute to brain stem control of nociceptive spinal dorsal horn neurons. The inhibition appears to result in part from presynaptic inhibition of afferents to dorsal horn neurons.
authors.affiliation: Departments of Neurology and Physiology and the W. M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, California 94143-0114, USA.
authors.forename: D
authors.initials: D
authors.lastname: Budai
authors.forename: H L
authors.initials: HL
authors.lastname: Fields
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006358:Hot Temperature; D007478:Iontophoresis; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000503:physiopathology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000502:physiology*; D018847:Opioid Peptides / Q000494:pharmacology / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology; D010487:Periaqueductal Gray / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000503:physiopathology*; D013623:Tail / Q000294:innervation
chemical_list: D000316:Adrenergic alpha-Agonists; D000701:Analgesics, Opioid; C529311:CTAP octapeptide; D004745:Enkephalins; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010446:Peptide Fragments; D010455:Peptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D009270:Naloxone; D013004:Somatostatin; D016202:N-Methylaspartate; D003000:Clonidine; D007608:Kainic Acid; D001640:Bicuculline